Foamable otic pharmaceutical compositions

ABSTRACT

The present invention relates a foamable otic pharmaceutical compositions comprising oil-in water emulsions which comprise an antibiotic agent and a propellant gas. The pharmaceutical compositions are administered to the ear as foam for treating ear disorders.

FIELD OF THE INVENTION

The present invention relates to foamable otic pharmaceuticalcompositions comprising oil-in-water emulsions which comprise anantibiotic agent and a propellant gas. The pharmaceutical compositionsare administered to the ear in the form of foam for treating eardisorders.

BACKGROUND OF THE INVENTION

Otitis externa which involves the ear canal portion of the external earis a common otologic problem occurring in humans mainly during hot andhumid weather. Otitis externa is five times more frequent in swimmersthan in non-swimmers. It is an acute or chronic inflammation of theepithelium of the external ear canal. It may develop anywhere from thetympanic membrane to the pinna. It is variably characterized byerythema, edema, increased sebum or exudates, and desquamation of theepithelium. In later stages, suppuration occurs in the ear canal andhearing may be decreased. Over 90% of cases of acute Otitis Externa(AOE) are due to bacterial infections.

Otitis externa is the most common disease of the ear canal in dogs andcats, and is occasionally seen in rabbits (in which it is usually due tothe mite Psoroptescuniculi).

Otitis media involves infections of the middle ear and it is a verycommon otologic problem in adults and particularly in children. It hasbeen estimated that nearly 95% of all children experience one or moreepisodes of otitis by age 9, and that about 15% of all visits bychildren to pediatricians are due to otitis media. In children, thedisease is often associated with upper respiratory afflictions whichtrigger a transudate secretion response in the Eustachian tube andmiddle ear. Bacteria and viruses migrate from the naso-pharynx to themiddle ear via the Eustachian tube, and can cause the Eustachian tube tobecome blocked, preventing ventilation and drainage of the middle ear.

The common treatment of AOE consists of topical antibiotics, with orwithout steroids, analgesia and water avoidance. Otic preparations aregenerally supplied in the form of ear drops. Antibiotic agents in eardrops include aminoglycosides (mainly neomycin) in combination withpolymyxin B and hydrocortisone or fluoroquinolones such as ciprofloxacinand ofloxacin.

Ciprofloxacin is a safe and efficacious antibacterial fluoroquinoloneactive against a broad spectrum of gram-positive and gram-negativebacteria. Ciprofloxacin is present as Ciprofloxacin base andCiprofloxacin HCl.

Due to its proven safety and lack of ototoxicity, sterile ciprofloxacinear drops are prescribed to treat patients with AOE with intact ornon-intact tympanic membrane. Topical otic compositions containing acombination of either ciprofloxacin and hydrocortisone or ciprofloxacinand dexamethasone are sold under the name of CIPRO HC™ and CIPRODEX™,respectively, by Alcon Laboratories, Inc.

U.S. Pat. No. 5,843,930 to Purwar et al. discloses a liquidnon-ototoxic, topical, otic pharmaceutical composition for the treatmentof otitis externa and otitis media which comprises ciprofloxacin, anon-ionic viscosity augmenter, a preservative, water sufficient toproduce an aqueous composition, hydrocortisone in aqueous suspension,lecithin, and polysorbate 20 to 80. U.S. Pat. No. 5,843,930 furtherdiscloses methods for treating otitis which comprise administering theotic pharmaceutical composition topically into the ear.

U.S. Pat. No. 6,359,016 to Singh et al., discloses aqueous suspensionformulations comprising ciprofloxacin, dexamethasone, sodium chloride asan ionic tonicity agent, a nonionic polymer, and a nonionic surfactant.The formulations according to U.S. Pat. No. 6,359,016 have a pH from 3-5that can be adjusted by NaOH/HCl and comprise the buffering system ofsodium acetate and acetic acid. According to U.S. Pat. No. 6,359,016,the formulations may further comprise quaternary ammonium halide as apreservative and a chelating agent.

U.S. Pat. No. 6,462,033 to Singh discloses method for preparing atopical composition comprising ciprofloxacin and hydrocortisone. Thecompositions of U.S. Pat. No. 6,462,033 have excellent physicalstability attributed to the method of their preparation, i.e.,hydrocortisone is dispersed with lecithin and optionally with apolysorbate surfactant for greater than 45 minutes prior to combininghydrocortisone with the remainder of the composition.

U.S. Pat. No. 6,730,288 to Abram discloses pharmaceutical aerosol foamcompositions which include a pharmaceutically active ingredient, anocclusive agent, an aqueous solvent, and an organic cosolvent, whereinthe pharmaceutically active ingredient being insoluble in both water andthe occlusive agent. The pharmaceutical compositions according to U.S.Pat. No. 6,730,288 are useful for topical administration of thepharmaceutically active ingredients on the skin.

U.S. Pat. No. 7,078,058 to Jones et al. discloses foamablepharmaceutical compositions comprising a corticosteroid, a quick-breakfoaming agent, a propellant and a buffering agent. According to U.S.Pat. No. 7,078,058, the quick-break foaming agent comprises an aliphaticalcohol, water, a fatty alcohol and a surface active agent. Thecompositions of U.S. Pat. No. 7,078,058 are especially well-suited foruse in the treatment of various skin diseases, and in particularly inthe treatment of scalp psoriasis.

U.S. Pat. No. 7,186,416 to Popp et al. discloses foamable deliverysystems which comprise a solvent composition, a surfactant composition,a propellant and an acid, particularly useful for dermatologicaladministration of corticosteroids and antifungal agents.

U.S. Pat. No. 7,700,076 to Tamarkin et al. discloses an alcohol-freecosmetic or pharmaceutical foam composition comprising water, ahydrophobic solvent, a surface-active agent, a gelling agent, an activecomponent selected from the group of urea, hydroxyl acid, and atherapeutic enhancer and a propellant. The foam according to U.S. Pat.No. 7,700,076 further comprises active agents and excipients withtherapeutic properties having enhanced skin penetration.

U.S. Pat. No. 8,030,362 to Eilat discloses a pharmaceutical compositionfor the treatment of an ear disorder in a form selected from foam andmousse comprising: a pharmaceutical agent known to affect an eardisorder; a pharmaceutically acceptable carrier comprising a dispersingagent that is a foam forming agent; and a dispensing device adapted forthe dispensing of the pharmaceutical agent admixed with the carrier tothe external auditory meatus.

International Patent Application Publication No. WO 2010/143186 assignedto the applicant of the present invention discloses a foamable oticpharmaceutical composition comprising an oil-in-water emulsion whichcomprises a fluoroquinolone, a hydrophobic solvent, an emulsifier and/ora synthetic surfactant, a stabilizing agent, a polar co-solvent, andwater; and a compressed propellant gas, wherein the composition packagedin a container is adapted to form foam after dispensing from thecontainer, the foam having a density of about 0.1 gr/ml to about 0.5gr/ml.

U.S. Patent Application Publication No. 2006/0233721 discloses afoamable oil-in-water emulsion composition which includes: (a) an oilglobule system selected from the group consisting of oil bodies andsub-micron oil globules; (b) about 0.1% to about 5% by weight of atleast one stabilizing agent selected from the group consisting of anon-ionic surfactant having an HLB value between 9 and 16, an ionicsurfactant, and a polymeric agent; and (c) a liquefied or compressed gaspropellant.

There is an unmet need for formulations comprising clinicallyefficacious compositions of an antibiotic agent which upon dispensingfrom a container form a stable dosage form retained in the patient's earso as to treat ear disorders.

SUMMARY OF THE INVENTION

The present invention provides foamable pharmaceutical compositionsuseful for otic administration which comprise an oil-in-water emulsioncomprising an antibiotic agent, optionally further comprising a steroidanti-inflammatory agent, and a propellant gas. Particularly, the presentinvention provides otic foamable pharmaceutical compositions comprisingan oil-in-water emulsion comprising a quinolone antibiotic agent such asciprofloxacin and a propellant gas, and use thereof for treating otitis.The present invention has improved properties in comparison topreviously known compositions intended for the same use, in particularin regard to the residence time and tackiness such that the foamformulation performs better and has increased efficacy in clinicaltrials.

It is now disclosed that foamable compositions of the inventioncomprising an oil-in-water emulsion and a compressed propellant gas,when dispensed from a container, formed a foam which collapsed in theear canal faster than when the same foam was applied to the skin. It isthus disclosed that a foamable composition applied into the ear canalmust form a foam having higher foam density than typical topical foamsto prevent quick foam collapse and subsequent quick leaking out from theear of the liquefied composition, as well as to enable administeringtherapeutic doses of the active agents into the small volume of the earcanal. Thus, the present invention provides foamable pharmaceuticalcompositions which form a foam having foam density higher than the foamdensity of commercially available topical foams, and as such are highlyuseful for otic administration.

The present invention now discloses that certain inactive ingredientsshould be avoided in order to produce a stable foam with the desiredresidence time in the ear. According to the principles of the presentinvention the foam will be sufficiently stable to remain within the earfor a minimum of at least one hour. According to the principles of theinvention the foam collapses within one hour to three hours ofadministration of the foam into the ear canal. Thus, while short chainalcohols should be avoided as these alcohols accelerate foam collapse,white petrolatum is preferably present in the foamable compositions inorder to stabilize the foam formed so as to obtain the desired foamcollapse rate in the ear canal.

The foamable pharmaceutical compositions of the present inventioncomprise a small number of excipients, all of which are approved forotic and/or topical use. By virtue of the small number of excipients,the present invention discloses cost-effective otic foamablecompositions. The compositions of the present invention produce atolerable sensation and did not reduce significantly the hearingcapability of human subjects treated with the compositions. Also, thefoamable compositions of the present invention which compriseciprofloxacin were found to be stable after long term storage, i.e., twoyears at room temperature, retaining the content of the quinoloneantibiotic. As the foamable compositions of the present invention formeda stable foam in the ear canal, such foamable compositions providedextended exposure of the subject to the quinolone antibiotics, therebyenabled reducing the administration frequency of the quinoloneantibiotics and hence prevented the exposure of the treated subject tohigher doses of the antibiotics. Moreover, the foamable pharmaceuticalcomposition of the present invention comprising ciprofloxacin as thesole active agent was found to cure subjects suffering from acute otitisexterna at lower doses of the antibiotics as compared to commerciallyavailable ear drops which comprise both ciprofloxacin and dexamethasone.Thus, not only was it discovered that the foamable compositions of thepresent invention provided a dosage form of the quinolone antibioticswith improved compliance, but moreover such compositions improved theantibiotic efficacy in treating otitis externa and surprisingly avoidedthe need for use of a steroid anti-inflammatory agent.

The foamable pharmaceutical composition of the present invention isuseful for treating external ear disorders and middle ear disorders.While dispensing the foam to the ear canal enables treating external eardisorders, dispensing the foam through a non-intact ear drum can enabletreating middle ear disorders. The foamable compositions of the presentinvention therefore comprise inactive ingredients approved for externalear disorders as well as safe for middle ear disorders. It isaccordingly disclosed that the foamable compositions of the presentinvention are devoid of propylene glycol as well as of other potentiallyototoxic excipients.

According to a first aspect, the present invention provides a foamableotic pharmaceutical composition comprising:

(a) an oil-in-water emulsion comprising:

-   -   (i) an antibiotic agent in an amount effective for antibacterial        action;    -   (ii) water in an amount of at least 75% (w/w);    -   (iii) mineral oil in an amount of no more 15% (w/w);    -   (iv) a synthetic surfactant pharmaceutically acceptable for otic        application;    -   (v) a foaming agent selected from a fatty alcohol and a fatty        acid;    -   (vi) white petrolatum; and

(b) a compressed propellant gas;

wherein the oil-in-water emulsion is devoid of organic polarco-solvents, the oil-in-water emulsion having osmolarity of about 280mOsm/L to about 320 mOsm/L, and wherein the composition packaged in acontainer is adapted to form a foam after dispensing from the container.

It is to be understood that the foamable otic pharmaceutical compositionof the present invention is stored as a liquid in an aerosol orpressurized container. Upon dispensing from the aerosol container, thefoamable otic pharmaceutical composition forms foam suitable forapplication into the ear. Thus, the pharmaceutical composition of thepresent invention when administered to the ear of a subject, e.g., ahuman or an animal, is in the form of a foam.

According to some embodiments, water is present in the composition in anamount ranging from 82% to 88% (w/w) of the total weight of theemulsion, alternatively in an amount ranging from 83% to 87% (w/w).

According to additional embodiments, mineral oil is present in thecomposition in an amount ranging from 7% to 10% (w/w) of the totalweight of the emulsion. According to a certain embodiment, mineral oilis present in an amount of 9% to 10% (w/w).

According to some embodiments, the synthetic surfactant is selected fromthe group consisting of polysorbate 80, polysorbate 60, polysorbate 20,PEG-40 stearate, tyloxapol, and combinations thereof. Each possibilityis a separate embodiment of the present invention. According toadditional embodiments, the synthetic surfactant is polysorbate 80present in an amount of about 1% to about 5% (w/w) of the total weightof the emulsion. According to further embodiments, the syntheticsurfactant is PEG-40 stearate present in an amount of about 0.25% toabout 2% (w/w) of the total weight of the emulsion. According to someembodiment, the surfactant is a mixture of polysorbate 80 and PEG-40stearate present in an amount of about 1% to about 5% (w/w) and about0.25% to about 2% (w/w), of the total weight of the emulsion,respectively. Alternatively, polysorbate 80 and PEG-40 stearate arepresent in the emulsion in an amount of about 3% to about 5% (w/w) andabout 1% to about 2% (w/w), of the total weight of the emulsion,respectively. According to a certain embodiment, the surfactant is amixture of polysorbate 80 and PEG-40 stearate present in an amount of 3%(w/w) and 1% (w/w) of the total weight of the emulsion, respectively.

According to still further embodiments, the foaming agent is a fattyalcohol or a fatty acid having at least 12 carbon atoms in the carbonchain. According to some embodiments, the foaming agent is selected fromthe group consisting of cetyl alcohol, stearyl alcohol, cetostearylalcohol, stearic acid, and combinations thereof. Each possibility is aseparate embodiment of the present invention. According to furtherembodiments, the foaming agent is present in an amount of about 0.25% toabout 2% (w/w) of the total weight of the emulsion. According to acertain embodiment, the foaming agent is cetyl alcohol present in anamount of about 1% to about 2% (w/w) of the total weight of theemulsion. According to a certain embodiment, cetyl alcohol is present inan amount of about 1% (w/w). According to other embodiments, the foamingagent is cetostearyl alcohol, stearyl alcohol, or stearic acid presentin an amount of about 0.25% to about 2% (w/w), alternatively in anamount of 0.5% to 1% (w/w) of the total weight of the emulsion.

According to yet further embodiment, white petrolatum is present in anamount that does not exceed 3% (w/w) of the total weight of theemulsion. According to certain embodiments, white petrolatum is presentin an amount ranging from about 0.1% to about 1% , alternatively from0.25% to 1% (w/w) of the total weight of the emulsion, furtheralternatively of 0.5% (w/w) of the total weight of the emulsion, thusproviding the desired foam stability. It is to be understood that thepresent composition can comprise white petrolatum and/or an organiccompound which can substitute while petrolatum, such organic compound isselected from the group consisting of alkanes, fatty acids, fatty acidalcohols, fatty acid esters, and alkyl ethers, and comprises at leasteight carbon atoms. Said organic compound is characterized by beingsolid at 22° C., by having a melting point of at least 35° C., and bybeing approved for otic use.

According to some embodiments, the antibiotic agent is a quinoloneantibiotic agent. According to additional embodiments, the quinoloneantibiotic agent is selected from the group consisting of ciprofloxacin,ofloxacin, moxifloxacin, finafloxacin, besifloxacin, JNJ-Q2,levofloxacin, lomefloxacin, nadifloxacin, norfloxacin, pefloxacin,rufloxacin, balofloxacin, gatifloxacin, grepafloxacin, levofloxacin,pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, clinafloxacin,gemifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, garenoxacin,delafloxacin, marbofloxacin, enrofloxacin, danofloxacin, difloxacin,ibafloxacin, orbifloxacin, sarafloxacin and salts thereof. Eachpossibility is a separate embodiment of the present invention. Accordingto further embodiments, the quinolone antibiotic agent is selected fromthe group consisting of ciprofloxacin, ofloxacin, moxifloxacin,levofloxacin, marbofloxacin, enrofloxacin, finafloxacin, besifloxacin,JNJ-Q2, orbifloxacin, delafloxacin, pradofloxacin and salts thereof.According to a certain embodiment, the quinolone antibiotic isciprofloxacin or a salt thereof. According to an exemplary embodiment,ciprofloxacin is ciprofloxacin hydrochloride. According to a furtherembodiment, the composition comprising a quinolone antibiotic is foranimal use. According to an exemplary embodiment, the quinolone foranimal use is marbofloxacin or enrofloxacin. The amount of the quinoloneantibiotic ranges from 0.1% to 1% (w/w) of the total weight of theemulsion, alternatively from 0.3% to 0.5% (w/w) of the total weight ofthe emulsion. According to a certain embodiment, the quinoloneantibiotic is ciprofloxacin hydrochloride present in an amount of 0.3%to 0.4% (w/w) of the total weight of the emulsion. According to anexemplary embodiment, ciprofloxacin hydrochloride is present in anamount of 0.35% (w/w) of the total weight of the emulsion).

According to further embodiments, the antibiotic agent is selected fromthe group consisting of aminoglycosides, ansamycins, carbacephems,carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides,macrolides, monobactams, nitrofurans, oxazolidonones, penicillins,polypeptides, sulfonamides, and tetracyclines.

According to additional embodiments, the pharmaceutical composition canfurther comprise a steroid anti-inflammatory agent selected from thegroup consisting of dexamethasone, dexamethasone sodium phosphate,hydrocortisone, hydrocortisone acetate, prednisolone,methylprednisolone, prednisone, triamcinolone acetonide, mometasone,budesonide, fluocinolone acetonide, betamethasone, betamethasone sodiumphosphate, betamethasone valerate, cortisone acetate, isoflupredoneacetate, tixocortol pivalate, triamcinolone alcohol, amcinonide,desonide, fluocinonide, halcinonide, fluocortolone,hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasonedipropionate, betamethasone dipropionate, prednicarbate,clobetasone-17-butyrate,clobetasol-17-propionate, fluocortolonecaproate, fluocortolone pivalate, and fluprednidene. Each possibility isa separate embodiment of the present invention. According to a certainembodiment, the steroid anti-inflammatory agent is dexamethasone. Theanti-inflammatory steroid is present in the composition in an amounteffective for anti-inflammatory action. Such amount typically rangesfrom 0.01% to 3% (w/w) of the total weight of the emulsion. According toa certain embodiment, the anti-inflammatory steroid is dexamethasonepresent in an amount of 0.1% (w/w) of the total weight of the emulsion.

According to yet further embodiments, the pharmaceutical compositionfurther comprises a tonicity or an osmolarity adjusting agent. Thetonicity or osmolarity adjusting agent is selected from the groupconsisting of salts e.g., sodium chloride, potassium chloride, andsugars, e.g., mannitol, dextrose, sorbitol. According to a certainembodiment, the tonicity agent is sodium chloride.

According to further embodiments, the pharmaceutical composition of thepresent invention further comprises at least one excipient selected fromthe group consisting of a preservative, a pH modifying agents, e.g.,acetic acid and sodium hydroxide or a buffering system to achieve thedesired pH, disodium edetate, and an antibacterial agent. According toanother embodiment, the preservative is benzalkonium chloride. Accordingto still further embodiment, the antibacterial agent is boric acid.

According to still further embodiments, the pH of the pharmaceuticalcomposition ranges from about 4 to about 5. According to a certainembodiment, the pH of the pharmaceutical composition ranges from 4.3 to4.8.

According to yet further embodiments, the propellant gas is volatilehydrocarbons such as butane, propane, isobutane, and mixture thereof.The amount of the compressed propellant gas in the pharmaceuticalcomposition ranges from about 1% to about 8% by weight of thecomposition, alternatively from about 2% to about 6%, and furtheralternatively 4% by weight of the composition. It is to be understoodthat gas propellants such as, for example, hydrofluoroalkanes,chlorofluoroalkanes, dimethyl ethers, and methyl ethers can also be usedas propellant gas in the compositions of the present invention.

According to yet further embodiments, the foamable otic pharmaceuticalcomposition further comprises an analgesic agent or an anesthetic agent.Among the analgesic agents, antipyrine is preferred, and among theanesthetic agents, benzocaine, tetracaine, and procaine are preferred.Each possibility is a separate embodiment of the present invention.

According to still further embodiments, the composition is for animaluse and further comprises an antifungal agent. Among the antifungalagents, nystatin, clotrimazole, miconazole, ketoconazole, fluconazole,thiabendazole, econazole, clomidazole, isoconazole, tioconazole,sulconazole, bifonazole, oxiconazole, fenticonazole, omoconazole,sertaconazole, flutrimazole, posaconazole can be used. Each possibilityis a separate embodiment of the present invention. According to certainembodiments, nystatin, clotrimazole, miconazole, ketoconazole,fluconazole, and thiabendazole are preferred.

According to yet further embodiments, the foamable otic composition isfor animal use and can further comprise an insecticide agent. Among theinsecticide agents, pyrethrins, pyrethroids, piperonyl butoxide, andN-octyl bicycloheptene dicarboximide, or a combination thereof can beused. Each possibility is a separate embodiment of the presentinvention.

According to some embodiments, the foamable otic pharmaceuticalcomposition comprises:

(a) an oil-in-water emulsion comprising:

-   -   (i) ciprofloxacin HCl in an amount of 0.35% (w/w) of the total        weight of the emulsion;    -   (ii) water in an amount of 82% to 88% (w/w) of the total weight        of the emulsion;    -   (iii) mineral oil in an amount of 7% to 10% (w/w) of the total        weight of the emulsion;    -   (iv) a synthetic surfactant selected from the group consisting        of polysorbate 80 in an amount of about 1% to about 5% (w/w),        and PEG-40 stearate in an amount of about 0.25% to about 2%        (w/w) of the total weight of the emulsion;    -   (v) cetyl alcohol in an amount of about 0.25% to about 2% (w/w)        of the total weight of the emulsion;    -   (vi) white petrolatum in an amount of about 0.1% to about 1%        (w/w) of the total weight of the emulsion; and

(b) a compressed propellant gas in an amount of about 1% to about 8%(w/w) of the total weight of the composition;

According to additional embodiments, the foamable otic pharmaceuticalcomposition comprises an oil-in-water emulsion comprising: ciprofloxacinHCl in an amount of 0.35% (w/w), water in an amount of 84% to 87% (w/w),mineral oil in an amount of 7% to 10% (w/w), polysorbate 80 in an amountof 3% to 5% (w/w), PEG-40 stearate in an amount of 1% to 2% (w/w), cetylalcohol in an amount of 1% to 2% (w/w), white petrolatum in an amount of0.25% to 0.5% (w/w) of the total weight of the emulsion, optionallyfurther comprising at least one excipient selected from the groupconsisting of sodium chloride, benzalkonium chloride, disodium edetate ,acetic acid, boric acid, and sodium hydroxide. According to an exemplaryembodiment, the pharmaceutical composition can further comprisedexamethasone in an amount of about 0.1% (w/w) of the total weight ofthe emulsion.

According to additional embodiments, sodium choride is present in anamount of 0.5% (w/w), benzalkonium chloride is present in thecomposition in an amount of 0.01% (w/w), disodium edentate is present inan amount of 0.1% (w/w), acetic acid is present in an amount of 0.1%(w/w), boric acid is present in an amount of 0.01% to 0.04% (w/w) of thetotal weight of the emulsion, and sodium hydroxide is present in anamount to achieve a pH of the pharmaceutical composition of about 4 toabout 5 before adding the compressed propellant gas.

According to a certain embodiment, the oil-in-water emulsion comprises:

Ingredient % (w/w) Water 84.3 Mineral oil 9 Polysorbate 80 (Tween 80) 3PEG-40 stearate 1 Cetyl alcohol 1 White petrolatum 0.5 Acetic acid 0.1NaOH 0.025 EDTA (disodium edetate) 0.1 Benzalkonium chloride 0.01 Boricacid 0.03 NaCl 0.5 Ciprofloxacin Hydrochloride 0.35

According to another embodiment, the oil-in-water emulsion comprises:

Ingredient % (w/w) Water 86.5 Mineral oil 7 Polysorbate 80 (Tween 80) 3PEG-40 stearate 1 Cetyl alcohol 1 White petrolatum 0.25 Acetic acid 0.1NaOH 0.025 EDTA (disodium edetate) 0.1 Benzalkonium chloride 0.01 Boricacid 0.03 NaCl 0.5 Ciprofloxacin Hydrochloride 0.35 Dexamethasone 0.1

According to a further aspect, the present invention provides a methodfor treating an ear disorder comprising administering to the ear canalof a subject in need of such treatment a therapeutically effectiveamount of the foamable otic pharmaceutical composition according to theprinciples of the present invention.

According to some embodiments, the subject is a human. According toadditional embodiments, the subject is an animal. According to furtherembodiments, the animal is a domestic pet animal. According to certainembodiments, the domestic pet animal is a dog or a cat.

According to additional embodiments, the ear disorder is selected fromthe group consisting of external ear disorder, middle ear disorder andinner ear disorder. Each possibility is a separate embodiment of thepresent invention. According to a certain embodiment, the ear disorderis otitis externa (swimmer's ear). According to another embodiment, theear disorder is otitis media. According to additional embodiment, theotitis externa is acute otitis externa. According to a furtherembodiment, the otitis externa is chronic otitis externa. According tofurther embodiments, the otitis media is selected from the groupconsisting of chronic suppurative otitis media and serous or secretoryotitis media due to tympanostomy tubes. Each possibility is a separateembodiment of the present invention.

According to yet further aspect, the present invention provides afoamable pharmaceutical composition for treating an ear disorder, thepharmaceutical composition comprises: (a) an oil-in-water emulsioncomprising: (i) an antibiotic agent in an amount effective forantibacterial action; (ii) water in an amount of at least 75% (w/w);(iii) mineral oil in an amount of no more than 15% (w/w); (iv) asynthetic surfactant pharmaceutically acceptable for otic use; (v) afoaming agent selected from a fatty alcohol and a fatty acid; (vi) whitepetrolatum; and (b) a compressed propellant gas; wherein theoil-in-water emulsion is devoid of organic polar co-solvents, theoil-in-water emulsion having osmolarity of about 280 mOsm/L to about 320mOsm/L, and wherein the oil-in-water emulsion and the compressedpropellant gas packaged in a container being adapted to form a foamafter dispensing from the container according to the principles of thepresent invention.

These and other embodiments of the present invention will be betterunderstood in relation to the description, examples and claims thatfollow.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a Kaplan-Meier survival curve of the estimated time-to-endof pain in Ciprodex® and FoamOtic treated subjects.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a foamable otic pharmaceuticalcomposition comprising: (a) an oil-in-water emulsion comprising: (i) anantibiotic agent or a salt thereof in an amount effective forantibacterial action; (ii) water in an amount of at least 75% (w/w);(iii) mineral oil in an amount of no more than 15% (w/w); (iv) asynthetic surfactant pharmaceutically acceptable for otic application;(v) a foaming agent; (vi) white petrolatum; and (b) a compressedpropellant gas; wherein the emulsion is devoid of organic polarco-solvents, the oil-in-water emulsion having osmolarity of about 280mOsm/L to about 320 mOsm/L, and wherein the composition being packagedin a container is adapted to form stable foam after dispensing from thecontainer.

It is now disclosed that short chain alcohols accelerated foam collapse.It is further disclosed that cellulose derivatives, such as hydroxyethylcellulose, as well as the emulsifier lecithin increased the tackiness ofsome compositions. The foamable composition of the present invention istherefore devoid of short chain alcohols, and according to a certainembodiment the composition is devoid of gelling agents, such ascellulose derivatives. According to additional embodiment, thecomposition is devoid of lecithin. It is further disclosed that glycerinmonostearate (GMS) was ineffective in stabilizing the foam. Thus, thecomposition is devoid of GMS and other organic polar co-solvents such aspropylene glycol.

It is further disclosed that the amounts of the excipients affected theemulsion stability as well as the foam quality and the foam collapserate. Thus, 1% (w/w) of the synthetic surfactant polysorbate 80 was notas effective as 3% or 5% (w/w) of the surfactant in stabilizing theemulsion and in improving foam quality.

The foaming agent cetyl alcohol in amounts of 0.25% and 0.5% (w/w) wasnot as effective in stabilizing the emulsion and in attenuating foamcollapse as 1% to 2% (w/w) which were shown to stabilize both theemulsion and the foam.

The synthetic surfactant PEG-40 stearate in amounts of 0.25% and 0.5%was not as effective as 1% to 2% (w/w) in stabilizing the emulsion or inattenuating foam collapse.

Mineral oil was found to improve foam quality and to stabilize the foamin amounts of 9% or 10% (w/w), while lower concentrations, e.g., 7% or8%, were found to be less effective.

White petrolatum in the amount of 1% (w/w) significantly attenuated foamcollapse, 0.5% and 0.25% (w/w) have a milder effect on the foam collapserate. Thus, the foamable pharmaceutical compositions of the presentinvention require certain excipients at a narrow concentration range soas to enable obtaining stable oil-in-water emulsions and stable foamwhich collapses in the ear canal within one hour to three hours postadministration.

The present invention provides foamable otic pharmaceutical compositionsfor use in treating ear disorders in humans and in animals. It is to beunderstood that the compositions for animal use can further compriseanti-fungal agents and/or miticide agents.

The term “emulsion” describes a dosage form consisting of a two-phasesystem comprised of at least two immiscible liquids, one of which isdispersed as droplets (internal or dispersed phase) within the otherliquid (external or continuous phase) generally stabilized with one ormore surfactants or emulsifying agents. Oil-in-water emulsion denotes anemulsion where the oil is the dispersed phase, and water is the externalor continuous phase.

The term “devoid” as used herein denotes an amount of an excipient whichis present in an amount of less than 0.1% (w/w) of the emulsion,preferably of less than about 0.05% (w/w), and more preferably it isabsent. In reference to polar co-solvents, the term “devoid” denotes anamount of less than 5% (w/w), preferably of less than 3% (w/w) or lessthan 2% (w/w), more preferably of less than 1% (w/w) of the total weightof the emulsion, and most preferably the polar co-solvents are absent.

The term “foam collapse rate” denotes the kinetics of foam coarseningand destruction resulting from the rupture of bubbles or from gastransfer from small to large bubbles and bubble coalescence occurringwithin the ear of a subject or within a tube.

The term “foam quality” denotes the appearance of the foam which isgraded from rich and creamy appearance (++++) to barely foamy, notcreamy appearance (+).

The term “stable emulsion” denotes a homogenous emulsion havingessentially no irreversible separation of the two phases.

The term “about” as used herein denotes ±10% of the value indicated.

The term “polar co-solvent” refers to an organic co-solvent, typicallysoluble in both water and oil. Examples of polar co-solvents includepolyols, such as glycerol (glycerin), propylene glycol, hexylene glycol,diethylene glycol, propylene glycol n-alkanols, and the like.

The term “therapeutically effective amount” is that amount of an activeagent which is sufficient to provide a beneficial effect to the subjectto which the active agent is administered. More specifically, atherapeutically effective amount means an amount of a quinoloneantibiotic and/or a steroid anti-inflammatory agent effective toalleviate or ameliorate the symptoms of an ear disorder of the subjectbeing treated. When otitis externa is treated, ear edema, ear pain, eardischarge, and tenderness to movement of the tragus/pinna are typicalsymptoms.

It is to be appreciated that the foamable composition of the presentinvention comprises water in an amount of 82% to 88% (w/w) of the totalweight of the emulsion. Alternatively the foamable composition comprisesbetween 83% and 87% (w/w) of the total weight of the emulsion, orbetween 84% to 85% (w/w) of the total weight of the emulsion.

The compositions of the present invention comprise a mineral oil.Mineral oil (e.g., Chemical Abstracts Service Registry number 8012-95-1)is a mixture of aliphatic, naphthalenic, and aromatic liquidhydrocarbons that derive from petroleum.

The terms “surfactant” or a “surface-active agent” include any agentlinking oil and water in the composition, in the form of emulsion. Ahydrophilic/lipophilic balance (HLB) of a surfactant indicates itsaffinity toward water or oil. The HLB scale ranges from 1 (totallylipophilic) to 20 (totally hydrophilic), with 10 representing an equalbalance of both characteristics. Hydrophilic surfactants formoil-in-water (o/w) emulsions. The HLB of a blend of two emulsifiersequals the weight fraction of emulsifier A times its HLB value plus theweight fraction of emulsifier B times its HLB value (weighted average).

According to some embodiments of the present invention, the surfactanthas a hydrophilic lipophilic balance (HLB) between about 9 and about 14,which is the required HLB (the HLB required to stabilize an O/W emulsionof a given oil) of most oils and hydrophobic solvents. Thus, in one ormore embodiments, the composition contains a single surface active agenthaving an HLB value between about 9 and 14, and in one or moreembodiments, the composition contains more than one surface activeagents and the weighted average of their HLB values is between about 9and about 14. Non-limiting examples of possible surfactants includepolysorbates, such as polyoxyethylene sorbitan monolaurate (polysorbate20), polyoxyethylene sorbitan monostearate (polysorbate 60) andpolyoxyethylene sorbitan monooleate (polysorbate 80); tyloxapol;glyceryl stearate; PEG-40 stearate; polyoxyethylene (POE) fatty acidesters; poly(oxyethylene) alkylyl ethers, such as poly(oxyethylene)cetyl ether, poly(oxyethylene) palmityl ether, polyethylene oxidehexadecyl ether, polyethylene glycol cetyl ether, and the like, and acombination thereof.

The composition of the present invention further comprises a foamingagent which can also act as an emulsifier as known in the art. It is tobe understood that the foaming agent enables obtaining foam with thedesired collapse rate. The foaming agent can be a fatty alcohol having12 or more carbons in its carbon chain, such as lauryl alcohol, myristylalcohol, cetyl alcohol, stearyl alcohol, cytostearyl alcohol, oleylalcohol, and linoleyl alcohol, or mixtures thereof. Other examples offatty alcohols are arachidyl alcohol (C20), behenyl alcohol (C22),1-triacontanol (C30), as well as alcohols with longer carbon chains (upto C50).

According to further embodiments, the antibiotic agent is a quinoloneantibiotic. According to additional embodiments, the antibiotic agent isselected from the group consisting of aminoglycosides such as amikacin,gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin,spectinomycin and the like; ansamycins such as geldanamycin, herbimycin,rifaximin, streptomycin; carbacephems such as loracarbef; carbapenemssuch as ertapenem, doripenem, imipenem/cilastatin, meropenem;cephalosporins such as cefadroxil, cefazolin, cefalotin or cefalothin,cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime,cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime,ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, ceftaroline fosamil,ceftobiprole; glycopeptides such as teicoplanin, vancomycin, telavancin;lincosamides such as clindamycin, lincomycin; lipopeptides such asdaptomycin; macrolides such as azithromycin, clarithromycin,dirithromycin, erythromycin, roxithromycin, troleandomycin,telithromycin, spiramycin; monobactams such as aztreonam; nitrofuranssuch as furazolidone, nitrofurantoin; oxazolidonones such as linezolid,posizolid, radezolid, torezolid; penicillins such as amoxicillin,ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin,flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin,penicillin g, penicillin v, piperacillin, temocillin, ticarcillin andcombination of penicillins with clavulanic acid; polypeptides such asbacitracin, colistin, polymyxin b; sulfonamides such as mafenide,sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine,sulfamethizole, sulfamethoxazole, sulfasalazine, sulfisoxazole,trimethoprim-sulfamethoxazole; tetracyclines such as tetracycline,demeclocycline, doxycycline, minocycline, oxytetracycline; arsphenamine,chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin,platensimycin, quinupristin/dalfopristin, thiamphenicol, tigecycline,tinidazole, and trimethoprim, or a combination thereof.

The “gelling agent” as referred to is defined as a naturally-occurringpolymeric material, a semi-synthetic polymeric material, or a syntheticpolymeric material useful as thickeners to provide higher viscosity ofthe composition than that of water. The naturally-occurring polymericmaterials include, for example, locust bean gum, sodium alginate, sodiumcaseinate, egg albumin, gelatin agar, carrageenan gum sodium alginate,xanthan gum, quince seed extract, tragacanth gum, starch, chemicallymodified starches and the like. The semi-synthetic polymeric materialsinclude, for example, cellulose ethers (e.g. hydroxyethyl cellulose,methyl cellulose, carboxymethyl cellulose, hydroxy propylmethylcellulose), polyvinylpyrrolidone, polyvinylalcohol, guar gum,hydroxypropyl guar gum, soluble starch, cationic celluloses, cationicguars and the like. The synthetic polymeric materials include, forexample, carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcoholpolyacrylic acid polymers, polymethacrylic acid polymers, polyvinylacetate polymers, polyvinyl chloride polymers, polyvinylidene chloridepolymers and the like.

The compositions of the present invention can be subjected tonano-sizing. Methods for nano-sizing of compositions are well known inthe art and include, but not limited to, nano-sizing by a high pressurehomogenizer.

The composition of the present invention can further comprise a varietyof formulation excipients. Such excipients can be selected, for example,from preservatives (e.g., benzalkonium chloride or benzyl alcohol); pHmodifying agents such as acid and base (e.g., acetic acid and sodiumhydroxide, and the like) or buffering agents to obtain the desired pH;tonicity agents (e.g., salts such sodium chloride); antibacterial agents(e.g., boric acid or zinc); disodium edetate; anti-oxidants (e.g.,□-tocopherol or a salt thereof, butylated hydroxytoluente, and thelike); and other formulation components used in the art of formulations.

Gas propellants are used to generate and administer the foamablecomposition as foam. Examples of suitable gas propellants includevolatile hydrocarbons such as butane, propane, isobutane or mixturesthereof, and fluorocarbon gases. The amount of the compressed propellantor liquefied gas is adapted to provide foam collapse within about 30minutes to about 2 hours after administration of the foam into the earof a subject. The amount of the compressed propellant gas is adapted toprovide foam density of about 0.05 gr/ml to about 0.15 gr/ml,alternatively from about 0.07 gr/ml to about 0.11 gr/ml, furtheralternatively from 0.07 gr/ml to 0.09 gr/ml.

The compositions of the present invention can be used for treatingexternal ear disorders, middle ear disorders and inner ear disorders.Each possibility is a separate embodiment of the present invention.External ear disorders include, but are not limited to, otitis externaincluding acute otitis externa and chronic otitis externa, blockage ofthe ear canal, otomycosis, granular myringitis, perichondritis, andbullous myringitis. Each possibility is a separate embodiment of thepresent invention. Middle ear disorders include, but are not limited to,otitis media including serous otitis media and chronic otitis media,mastoiditis, ruptured ear drum, and myringitis. Each possibility is aseparate embodiment of the present invention. Inner ear disordersinclude, but are not limited to, Meniere's disease and tinnitus. Eachpossibility is a separate embodiment of the present invention.

EXAMPLE 1

Foam Formulations and Characterization

The different foam formulations were evaluated for foam quality, pH,appearance after centrifugation, foam density, foam collapse rate invitro and in vivo, and sensory assessment of the foam in the ear asfollows:

Foam Quality:

Visual inspection used to characterize the grade of the resulting foamwas as follows:

-   -   Excellent (++++)—very rich and creamy in appearance;    -   Very good (+++)—rich and creamy in appearance.    -   Good (++)—rich and creamy in appearance, but have large bubble        structure;    -   Poor (+)—barely foamy, not creamy, liquid in appearance.        pH:

The pH was determined during the formulation preparation process and atthe foam level. The pH was also measured at different time points duringthe accelerated stability studies.

Centrifugation Test:

The test was aimed at assessing the emulsion stability at acceleratedconditions. High speed centrifugation was used to mimic the phaseseparation process that would occur as a result of time. The test wasperformed as follows: About 1 gr of emulsion formulation was weighed andspun in a microfuge tube for 10 minutes at 3,000 RPM (equivalent to X600g) or at 10,000 RPM (equivalent to X6700 g). The formulation appearancewas graded according to the degree of phase separation as follows:

Creaming (Cr.)—Upper layer-opaque, Lower layer-transparent ortranslucent, reversible situation [% Creaming describes the percentagethat occupies the upper layer portion]: Grade ++++ is equivalent to90%-100% creaming (negligible separation). Grade +++ is equivalent to60%-90% creaming. Grade ++ is equivalent to 30%-60% creaming. Grade + isequivalent to up to 30% creaming (significant separation).

Foam Density:

Foam was released from the pressurized canister into a pre-weighedgraduated cylinder and foam was allowed to expand to its maximal volume.The weight and the volume of the foam were recorded. Foam density wasdefined as the weight recorded divided by the final volume after foamexpansion. The test was performed and recorded 3 times independently.

Foam Collapse Rate in Vitro:

Foam collapse rate in vitro was determined by delivering the foamablecomposition into a transparent glass tube. The glass tube was pre-warmedand maintained at 40° C. for up to two hours. At different time pointsthe remaining foam volume was assessed visually and expressed atpercentage of the initial volume.

Foam Collapse Rate in Vivo:

Foam was introduced in the ear canal of healthy adult human subjects andthe time of application was recorded. The percentage of the remainingfoam was assessed at different time points for up to 3 hours. Thesubjects were allowed to continue their normal activities during thestudy.

Analytical Determination of Ciprofloxacin and Dexamethasone in theFormulations:

To determine the amount of ciprofloxacin or dexamethasone present in thefoam formulations, an Ultra Performance Liquid Chromatography (UPLC)based method was used to test the emulsions (devoid of propellant)designated herein below bulk formula or bulk emulsion as well as thefoam formulations which contained the propellant.

Foam Development:

Table 1 lists the excipients used for formulation development.

TABLE 1 Formulation excipients. Excipient Role in formulation Oil phaseMineral oil Oil, emollient Cetyl alcohol Foaming agent, emulsifierCetostearyl alchol Foaming agent, emulsifier Stearyl alcohol Foamingagent, emulsifier Stearic acid Foaming agent, emulsifier PEG-40 stearateSurfactant Water phase Water Solvent Polysorbate 80 Surfactant Aceticacid pH modifying agent Benzalkonium chloride Preservative Sodiumhydroxide pH modifying agent Sodium chloride Tonicity agent DisodiumEDTA Boric acid Propane, Butane, Isobutane PropellantPreparation of Foamable Formulations5. Water Phase

-   -   Acetic acid, NaOH, EDTA, Boric acid, NaCl, benzalkonium        chloride, and Polysorbate 80 were added to water and stirred on        a hot plate while heating to 70° C. until a clear solution was        obtained.    -   Ciprofloxacin HCl was then added and stirred for 5 minutes at        70° C.        6. Oil Phase    -   Mineral oil, PEG 40 stearate, cetyl alcohol and white petrolatum        were stirred on a hot plate while heating to 70° C. until a        clear phase was obtained (5-10 minutes).        7. Emulsification/Homogenization    -   The oil phase was added to the water phase while homogenizing        using a Kinematica Polytron homogenizer (Model PT10-35). The        homogenizing continued for additional 3 minutes (for 2 kg        emulsion). Thereafter, the emulsion was mixed at 450 rpm, then        at 300 rpm at room temperature with impeller (stirrer diameter        6.5 cm, shaft length 32 cm). The pH was determined and adjusted        as needed. The emulsion was weighted and water was added if        needed.        8. Packaging Procedure    -   Canisters and valves were washed with ethanol and filled with        12±1 gr of the emulsion. The valves were crimped on the        canister. Hydrocarbon propellant mixture (0.48±0.1 gr; 4% w/w of        the final formulation) was added.        Results    -   Three formulations were initially prepared and are presented in        Table 2.

TABLE 2 Formulations #62, 65 and 67. Formulation Formulation FormulationIngredient #62 (%) #65 (%) #67 (%) Ciprofloxacin HCl 0.35 0.35 0.35Dexamethasone 0.1 0.1 0.1 Water 85 85 86 Mineral oil 7 7 7 Polysorbate80 3 2.4 2.4 PEG-40 stearate 0.5 1 0.5 Cetyl alcohol 1 1 0.5 Acetic acid0.1 0.1 0.1 Sodium hydroxide 0.025 0.025 0.025 EDTA 0.1 0.1 0.1Benzalkonium chloride 0.02 0.02 0.02 Boric acid 0.04 0.04 0.04 Sodiumchloride 0.1 0.1 0.1

Formulations #62 and #65 resulted in foam which collapsed within 20minutes after dispensing to a tube at 40° C. or to the ear canal,dripping out from the ear once collapsed. Formulation #67 resulted infoam which collapsed even faster, i.e., within few minutes in a tube at40° C. and in the ear canal. As the amount of cetyl alcohol informulation #67 was half the amount in formulations #62 and #65, theresults indicated that the amount of cetyl alcohol should be of about 1%(w/w) to obtain stable foam.

In the course of developing foamable compositions which form stable foamin the ear canal, various excipients such as while petrolatum, glycerol,glycerin monostearate, lecithin, and hydroxyethyl cellulose (HEC) havebeen added to the compositions.

TABLE 3 Formulations #32, 36, 38, 40 and 77. #32 #36 #38 #40 #77Ingredient % (w/w) % (w/w) % (w/w) % (w/w) % (w/w) Water 78 77.8 77.8587.95 87.5 Mineral oil 5 5 5 5 7 Polysorbate 80 3 3 3 3 3 PEG-40stearate 1 1 1 1 1 Cetyl alcohol 1 1 1 1 1 White petrolatum 2 2 2 2Glycerol 10 10 10 Glycerin monostearate 0.2 Lecithin 0.15 Citric acid0.05 Hydroxyethylcellulose 0.1

Formulation #36 to which glycerin monostearate (GMS) was added in orderto increase foam consistency did not form stable foam as it collapsedwithin few minutes. Formulations #38 and #77 to which lecithin or HECwere added, respectively, were sticky. Formulation #40 to which citricacid was added resulted in foam that collapsed within few minutes.

In order to stabilize the foam, the presence of PEG-40 stearate wasevaluated.

TABLE 4 Formulations #57, 58, 61 and 62. Ingredient #57 #58 #61 #62Water 82.5 84.5 85.5 85 Min. Oil 7 7 7 7 Polysorbate 80 3 3 3 3PEG-40-stearate 1 1 0 0.5 Cetyl Alcohol 1 1 1 1 White Petrolatum 2 0 0 0Glycerin 0 0 0 0 Acetic Acid 0.1 0.1 0.1 0.1 NaOH 0.025 0.025 0.0250.025 EDTA 0.01 0.01 0.01 0.1 BAC 0.01 0.01 0.01 0.01 Boric Acid 0.030.03 0.03 0.03 Ciprofloxacin 0.35 0.35 0.35 0.35 Dexamethasone 0.1 0.10.1 0.1 NaCl 0.9 0.9 0.9 0.9

Formulations #57 and 58 listed in Table 4 were found to form a stablefoam under in-vitro conditions while formulation #61 formed a foam thatcollapsed quickly (quick-breaking) under these conditions. The resultsindicated that PEG-40 Stearate is essential for foam stability.Formulation #62 formed a stable foam yet when applied into the ear itcollapsed within approximately 10 minutes and a fraction of theformulation dripped out of the ear.

Further experiments were performed aiming at developing foamablecompositions which show foam collapse 60 minutes after dispensing from acontainer into the ear and which do not drain out of the ear canal onceliquefied.

TABLE 5 Formulations #104, 109, 111 and 112. #104 #109 #111 #112Ingredient % (w/w) % (w/w) % (w/w) % (w/w) Water 85.8 86.3 86.5 86.5Mineral oil 7 7 7 7 Polysorbate 80 3 3 3 3 PEG-40 stearate 1 1 1 1 Cetylalcohol 1 1 1 1 White petrolatum 1 0.5 0.25 0.1 Acetic acid 0.1 0.1 0.10.1 NaOH 0.025 0.025 0.025 0.025 EDTA (disodium edetate) 0.1 0.1 0.1 0.1Benzalkonium chloride 0.01 0.01 0.01 0.01 Boric acid 0.03 0.03 0.03 0.03NaCl 0.9 0.9 0.9 0.9 Ciprofloxacin HCl 0.35 0.35 0.35 0.35 Dexamethasone0.1 0.1 0.1 0.1

Formulation #104 which contained 1% white petrolatum (w/w) of the totalweight of the emulsion formed stable foam that showed minor collapse inthe ear three hours after dispensing from the container. In contrast,formulation #112 which contained 0.1% (w/w) white petrolatum, collapsedwithin 30 to 60 minutes after dispensing from the container.Formulations #109 and #111 were found to show the desired foamstability, namely they showed significant collapse in the ear canal 60to 120 minutes after dispensing.

EXAMPLE 2

Optimization of Formulation Excipients

Adjustment of Osmolarity

In order to achieve the required osmolarity (˜300 mOsm/L), increasingamounts of sodium chloride were added to formula #62 (prepared in theabsence of sodium chloride). The osmolarity of the formulae was measuredusing the Advanced® Model 3300 Osmometer. The results indicated thataddition of sodium chloride at a final concentration of 0.5% w/w toformula #62 increased the osmolarity from 91 mOsm/L to 285 mOsm/L. Itwas further demonstrated that addition of 0.25% w/w of white petrolatumincreased the osmolarity by 15 mOsm/L. Therefore, formulae comprising0.5% w/w sodium chloride and up to 0.5% w/w white petrolatum are withinthe acceptable range of osmolarity.

Adjustment of Polysorbate 80

Optimization of Polysorbate 80 was performed on formulation #109.

TABLE 6 Formulation #109 with increasing amounts of polysorbate 80. #109#109-Control #109 Polysorbate 80 Polysorbate 80 Polysorbate 80 (1%) (3%)(5%) Ingredients % (w/w) % (w/w) % (w/w) Water 88.735 86.735 84.735Mineral Oil 7 7 7 Polysorbate 80 1 3 5 PEG-40 stearate 1 1 1 CetylAlcohol 1 1 1 White Petrolatum 0.5 0.5 0.5 Acetic Acid 0.1 0.1 0.1 NaOH0.025 0.025 0.025 EDTA 0.1 0.1 0.1 Benzalkonium Chloride 0.01 0.01 0.01Boric Acid 0.03 0.03 0.03 NaCl 0.5 0.5 0.5 Total 100 100 100

TABLE 7 Foam characteristics of the formulations of Table 6. Separationof bulk +++ ++++ ++++ formula-upon storage at 25° C. for 7 daysSeparation of bulk +++ ++++ ++++ formula-upon storage at 40° C. for 7days Centrifugation results ++++ +++ +++ 3,000 RPM Centrifugationresults +++ ++ +++ 10,000 RPM Foam quality +++ ++++ ++++ Foam collapseafter ++++ ++++ +++ storage at 5° C. for 7 days Foam collapse after ++++++++ ++++ storage at room temp for 7 days Foam collapse after ++++ ++++++++ storage at 40° C. for 7 days

As shown in Table 7, foam quality was reduced when the amount ofpolysorbate 80 was reduced to 1% (w/w) of the emulsion. In addition, theformulation which contained 1% polysorbate 80 showed higher separationthan that of formulations having higher amounts of polysorbate 80. Noadvantage was found when increasing the amount of polysorbate 80 from 3%to 5% (w/w of the total weight of the emulsion).

Adjustment of Cetyl Alcohol

To optimize the amount of cetyl alcohol, formulation #109 was preparedwith 0.25% to 1% (w/w) of cetyl alcohol.

TABLE 8 Formulation #109 with increasing amounts of cetyl alcohol. #109#109 Cetyl Cetyl #109-Control- #109 Alcohol Alcohol Cetyl Cetyl Alcohol0.25% 0.5% Alcohol 2.0% Ingredients % (w/w) % (w/w) % (w/w) % (w/w)Water 87.485 87.235 86.735 85.735 Mineral Oil 7 7 7 7 Polysorbate 80 3 33 3 PEG-40 stearate 1 1 1 1 Cetyl Alcohol 0.25 0.5 1 2 White Petrolatum0.5 0.5 0.5 0.5 Acetic Acid 0.1 0.1 0.1 0.1 NaOH 0.025 0.025 0.025 0.025EDTA 0.1 0.1 0.1 0.1 Benzalkonium 0.01 0.01 0.01 0.01 Chloride BoricAcid 0.03 0.03 0.03 0.03 NaCl 0.5 0.5 0.5 0.5 Total 100 100 100 100

TABLE 9 Foam characteristics of the formulations of Table 8. Separationof bulk + ++ ++++ ++++ formula—upon storage at 25° C. for 7 daysSeparation of bulk + + ++++ ++++ formula—upon storage at 40° C. for 7days Centrifugation results + +++ +++ ++++ 3,000 RPM Centrifugationresults + ++ ++ ++++ 10,000 RPM Foam quality ++++ ++++ ++++ ++++ Foamcollapse after + +++ ++++ ++++ storage at 5° C. for 7 days Foam collapseafter + ++++ ++++ ++++ storage at room temp for 7 days Foam collapseafter + ++++ ++++ ++++ storage at 40° C. for 7 days

As shown in Table 9, foam collapse was accelerated when the amount ofcetyl alcohol was reduced to 0.25% or 0.5% (w/w of the total weight ofthe emulsion). In addition, the formulations having 0.25% or 0.5% (w/w)of cetyl alcohol showed higher separation compared to formulationshaving higher amounts of cetyl alcohol. Increasing the amount of cetylalcohol from 1% to 2% (w/w) did not have a significant effect on foamstability.

Adjustment of PEG-40 Stearate

TABLE 10 Formulation #109 with increasing amounts of PEG-40 stearate.#109 #109 #109-Control- #109 PEG-40 PEG-40 PEG-40 PEG-40 stearatestearate Stearate stearate 0.25% 0.5% 1% 2% Ingredients % (w/w) % (w/w)% (w/w) % (w/w) Water 87.485 87.235 86.735 85.735 Mineral Oil 7 7 7 7Polysorbate 80 3 3 3 3 PEG-40 stearate 0.25 0.5 1 2 Cetyl Alcohol 1 1 11 White Petrolatum 0.5 0.5 0.5 0.5 Acetic Acid 0.1 0.1 0.1 0.1 NaOH0.025 0.025 0.025 0.025 EDTA 0.1 0.1 0.1 0.1 Benzalkonium Chloride 0.010.01 0.01 0.01 Boric Acid 0.03 0.03 0.03 0.03 NaCl 0.5 0.5 0.5 0.5 Total100 100 100 100

TABLE 11 Foam characteristics of the formulations of Table 10.Separation of bulk ++++ ++++ ++++ ++++ formula—upon storage at 25° C.for 7 days Separation of bulk ++++ ++++ ++++ ++++ formula—upon storageat 40° C. for 7 days Centrifugation results ++++ ++++ +++ ++++ 3,000 RPMCentrifugation results +++ ++ ++ + 10,000 RPM Foam quality ++++ ++++++++ ++++ Foam collapse after ++ +++ ++++ ++++ storage at 5° C. for 7days Foam collapse after ++++ ++++ ++++ ++++ storage at room temp for 7days Foam collapse after ++++ ++++ ++++ ++++ storage at 40° C. for 7days

As shown in Table 11, foam collapse of the formulations stored at 5° C.for 1 week was accelerated when the amount of PEG-40 stearate wasreduced to 0.25% and 0.5% (w/w of the total weight of the emulsion).Based on the results of the centrifugation assay, increasing the amountof PEG-40 stearate to 2% (w/w) increased the separation of theformulation.

Adjustment of the Concentration of Mineral Oil Formula

TABLE 12 Formulation #109 with increasing amounts of mineral oil.#109-Control #109 #109 #109 Mineral oil Mineral oil Mineral oil Mineraloil 7% 8% 9% 10% Ingredients % (w/w) % (w/w) % (w/w) % (w/w) Water86.735 85.735 84.735 83.735 Mineral Oil 7 8 9 10 Polysorbate 80 3 3 3 3PEG-40 stearate 1 1 1 1 Cetyl Alcohol 1 1 1 1 White Petrolatum 0.5 0.50.5 0.5 Acetic Acid 0.1 0.1 0.1 0.1 NaOH 0.025 0.025 0.025 0.025 EDTA0.1 0.1 0.1 0.1 Benzalkonium 0.01 0.01 0.01 0.01 Chloride Boric Acid0.03 0.03 0.03 0.03 NaCl 0.5 0.5 0.5 0.5 Total 100 100 100 100

TABLE 13 Foam characteristics of the formulations of Table 12.Separation of bulk ++++ ++++ ++++ ++++ formula—upon storage at 25° C.for 7 days Separation of bulk ++++ ++++ ++++ ++++ formula—upon storageat 40° C. for 7 days Foam quality after + ++ +++ ND 1 month storage at5° C. Foam collapse after + ++ ++++ ND storage at 5° C. for 14 days Foamcollapse after ++++ ++++ ++++ ++++ storage at 40° C. for 1 month

As shown in Table 13, foam collapse was accelerated upon storage at 5°C. for 1 month of all the formulations tested. However, increasing theamount of mineral oil from 7% to 9% improved the physical stability ofthe foam at low temperatures.

Replacements for Cetyl Alcohol

TABLE 14 Formulation #109 with various foaming agents. #109 withCetostearyl #109 #109 alcohol with Stearyl alcohol with Stearic acid[0.25%-1%] [0.25%-1%] [0.25%-1%] Ingredients % (w/w) % (w/w) % (w/w)Water [83.7-87.4] 84.735 85.735 Mineral Oil 7 10 9 Polysorbate 80 3 3 3PEG-40 stearate 1 1 1 (polyoxyl 40 stearate) Cetyl Alcohol — — —Cetostearyl [0.25-1.0]  — — alcohol Stearyl alcohol — [0.25-1.0] —Stearic acid — — [0.25-1.0] White Petrolatum 0.5 0.5 0.5 Acetic Acid 0.10.1 0.1 NaOH 0.025 0.025 0.025 EDTA 0.1 0.1 0.1 Benzalkonium 0.01 0.010.01 Chloride Boric Acid 0.03 0.03 0.03 NaCl 0.5 0.5 0.5 Total 100 100100

All formulations showed that cetostearyl alcohol, stearyl alcohol orstearic acid at amounts of 0.5% and 1.0% (w/w of the total weight of theemulsion) can replace cetyl alcohol. The results showed comparable foamquality and foam collapse rate of formulation #109 that has 9% mineraloil.

EXAMPLE 3

Stability of Formulations

Stability of Ciprofloxacin in the Formulations

Stability of ciprofloxacin in formulation #109 (see Table 15 hereinabove) was evaluated at controlled room temperature and at acceleratedaging conditions. The formulation was packed in aluminum canisters,crimped with commercial valves and incubated at 25° C. or 40° C. fordifferent periods of time. Samples from the formulations were taken atzero time (0 months) and after six months of storage and tested by UPLCfor the content of ciprofloxacin and its known related/degradationproducts.

TABLE 15 Formulations #109 and #109-F used for stability studies #109#109-F Ingredients % (w/w) % (w/w) Water 86.385 86.285 Mineral Oil 7 7Polysorbate 80 3 3 Peg-40 stearate 1 1 Cetyl Alcohol 1 1 WhitePetrolatum 0.5 0.5 Acetic Acid 0.1 0.1 NaOH 0.025 0.025 EDTA 0.1 0.1Benzalkonium Chloride 0.01 0.01 Boric Acid 0.03 0.03 NaCl 0.5 0.5Ciprofloxacin HCl 0.35 0.35 Dexamethasone — 0.1 Total 100 100

TABLE 16 Stability of Ciprofloxacin in formula #109 CiprofloxacinCiprofloxacin Related Substances, % of % of label claim Sample StorageStorage label Ciprofloxacin Ciprofloxacin label conditions period % w/wclaim Ethylenediamine Formamide Total #109-C 25° C. 6 months 0.338 96.50.00 0.00 0.00 #109-C 40° C. 6 months 0.343 98.0 0.07 0.00 0.07

The results presented in Table 16 show that the concentration ofCiprofloxacin did not significantly change upon incubation at 25° C. or40° C. for up to 6 months. Furthermore, no significant increase wasfound in the level of substances related to the degradation ofCiprofloxacin. The results thus demonstrate that the formulationdeveloped is chemically stable and displays a potentially longshelf-life. It is well known that storage at 40° C. for 6 months isconsidered indicative for the stability of a product for not less than24 months at room temperature.

Stability of Ciprofloxacin and Dexamethasone in the Formulation

Stability of ciprofloxacin and dexamethasone in formulation #109-F (seeTable 15 herein above) was evaluated at controlled room temperature andat accelerated aging conditions. The formulation was packed in aluminumcanisters, crimped with commercial valves and incubated at 25° C. or 40°C. for different periods of time. Samples from the formulations weretaken at zero time (0 months) and at various time points up to threemonths of storage and tested by UPLC for the content of ciprofloxacinand dexamethasone. The results presented in Table 17 show that theconcentration of ciprofloxacin and dexamethasone did not significantlychange upon incubation at 25° C. or 40° C. for up to 3 months. Theresults demonstrate that the formulation #109-F is chemically stable anddisplays a potentially long shelf-life.

TABLE 17 Stability of Ciprofloxacin and Dexamethasone in formula #109-FStorage Formula 109-F conditions 0 months 1.5 months 3 monthsCiprofloxacin 25° C.  99.6% 99.1% 101.5% [% of label claim] 40° C. 99.6% 98.1%  95.3% Dexamethasone 25° C. 102.3% 107.2%  103.1% [% oflabel claim] 40° C. 102.3% 95.0%  94.3%

EXAMPLE 4

Antibiotic Activity of the Formulation

When attempting to validate a method for the microbial enumeration ofthe formulation according to the US Pharmacopeia, it was found thatformulation #109 (see Example 2 herein above) quickly killed all strainsof bacteria tested (Bacillus subtilis ATCC 6633, Staphylococcus aureusATCC 6538, and Pseudomonas aeruginosa ATCC 9027). Various approacheswere used including a massive dilution of the formula (at least 800fold), and a dilution 100 fold of the formulation followed by filtrationand rinse of the filter. In all cases the method could not be validatedsince the recovery of the inoculated bacteria did not meet thePharmacopeia requirements. Additional tests demonstrated that theantibiotic agent in the formulation was effectively rinsed off thefilters, yet due to its high concentration and quick killing action therecovery of bacteria was nil or insufficient. It was therefore concludedthat a variety of bacteria could not contaminate the formulation.Quantitative enumeration of fungi such as Candida albicans ATCC 10231and Aspergillus brasiliensis ATCC 16404 indicated that formulations(formulation #109 of EXAMPLE 2 herein above) prepared using goodmanufacturing procedures were found to have less than 1 CFU/gr (i.e. theformulations were not contaminated).

In addition, challenge tests showed that the formulation can preventcontamination that may occur during use or during manufacturing of theproduct. As shown above, bacterial growth was unfeasible; thereforechallenge studies were performed with yeast and molds. The requirementsfor antimicrobial effectiveness are met if no increase from the initialcalculated count for yeast and molds occurs at 7, 14, and 28 days. Asshown in Table 18, in the case of formulation #109-C disclosed hereinabove, not only there was no increase in the initial count, but adrastic 5.0 log reduction for both yeast Candida albicans and the moldAspergillus brasiliensis was found after 14 days of storage.

TABLE 18 Antimicrobial effectiveness of formulation #109-C. CandidaAspergillus albicans brasiliensis (ATCC 10231) (ATCC 16404) Time point[CFU/gr] [CFU/gr] After inoculation and before 500000 280000 addition ofpropellant After addition of propellant 53000 59000 After 7 days <10 50After 14 days <10 <10 After 28 days <10 <10

The results of Table 16 indicate that if the product is accidentallycontaminated during the manufacturing, the preservative and theantibiotic agent present in the formulation will eliminate the microbesintroduced and the product will be uncontaminated.

EXAMPLE 5

Clinical Study

A clinical study for assessing the safety, efficacy, and clinicalnon-inferiority of once a day treatment with a foamable compositiondesignated formula #109-C (that contains only ciprofloxacin as theactive ingredient, see Table 19 herein below) in comparison to twicedaily application of a commercial ear drop suspension of ciprofloxacinand dexamethasone (Ciprodex® manufactured by Alcon Labs) in thetreatment of Acute Diffuse Otitis Externa (“Swimmer's ear”) wasconducted.

TABLE 19 Ingredients of formulation #109-C. #109-C Ingredients % (w/w)Water 84.385 Mineral Oil 9 Polysorbate 80 3 Peg-40 stearate 1 CetylAlcohol 1 White Petrolatum 0.5 Acetic Acid 0.1 NaOH 0.025 EDTA 0.1Benzalkonium Chloride 0.01 Boric Acid 0.03 NaCl 0.5 Ciprofloxacin HCl0.35 Total 100

The study was open-label, assessor-blinded, randomized, parallel,comparative and multicenter, enrolled 220 subjects aged 6 months andolder diagnosed with Otitis Externa of presumed bacterial origin.Inclusion and outcome criteria included the signs and symptoms of thedisease: ear edema, ear erythema, ear discharge, and tenderness tomovement of the tragus/pinna. The study, complying with GCP guidelines,was performed in 2 hospitals and 8 community clinics in Israel from Julyto October 2013. The subjects were randomized into one of the twotreatment groups: 1) once a day treatment with FoamOtic Cipro, i.e., theotic foam formulation #109-C; or 2) twice a day treatment withcommercial ear drops Ciprodex® manufactured by Alcon Labs. From the 220patients enrolled, 199 subjects were found eligible to be included inthe “Per Protocol” analysis set that consisted of 97 subjects that weretreated with the otic foam treatment and 102 subjects that were treatedwith ear drops.

Both treatments continued for 7 days. Microbial cultures were taken fromthe subjects at baseline visit (considered day 1), at a visit duringtreatment, and post-treatment at the test-of-cure visit (Visit 3, days8-11). Upon completion of the treatment, the signs and symptoms of theinfection were assessed and compared to baseline. Subjects wereconsidered “Cured” if the physician considered that no additionalantibiotic treatment was needed at the test of cure visit (Visit 3)while subjects were considered treatment “Failure” if an additionalantibiotic treatment was needed. In order to measure the time to end ofpain subjects were requested to fill twice daily a pain dairy accordingto a visual analogue scale (VAS) being zero (0) no pain and 10 thehighest conceivable pain. Data from young children was collected using a“Faces Pain Scale” with scores of 0, 2, 4, 6, 8, or 10, being ‘0’=‘nopain’ and ‘10’=‘very much pain’. Time to end of pain was defined as thetime lapsed from the first dose taken to the first instance in which thepain score reported is zero (0) being zero (0) all the subsequent painscores reported.

The results in Table 20 show that the cure rates of FoamOtic appliedonce daily and Ciprodex® applied twice daily were similar. Thepercentage of cured subjects was 94.85% in the foam treated group (92out of 97 subjects) and 96.08% in the Ciprodex® group (98 out of 102).The failure rates were 5.15% and 3.92% for the foam treated andCiprodex® treated group, respectively. The differences found were notstatistically significant (p-value of Fisher exact test 0.7429).

TABLE 20 Clinical results (per protocol analysis). Cure rate Failurerate (subjects that did not require (subjects that required Treatmentarm additional antibiotic therapy) additional antibiotic therapy)FoamOtic 94.85% (92/97)  5.15% (5/97)  Ciprodex ® 96.08% (98/102) 3.92%(4/102)

The results therefore indicate that once-daily treatment with the oticfoam (Formulation #109-C) which contains ciprofloxacin as the soleactive ingredient was as efficient as twice daily application ofcommercial ear drops which contain two active ingredients: ciprofloxacinand dexamethasone. It is to be emphasized that the concentration ofciprofloxacin in the foam formulation and in the ear drops wasidentical.

In addition, there were no differences in the levels of cure ratesobserved for FoamOtic and Ciprodex® in children and adults. In children(subjects aged 6 months to 18 years old) the cure rate achieved in thefoam-treated group was 96.30% while the cure rate in theCiprodex®-treated group was 95.74%. Similarly, in adults, the cure rateachieved by the Foam was 93.02% and in the Ciprodex® group was 96.36%(see Table 21). The differences found were not statistically significant(p-value of Fisher exact test 1.000 and 0.6512 for children and adults,respectively).

TABLE 21 Cure rates achieved in children and adults treated withFoamOtic or Ciprodex ® Cure rate Failure rate (subjects that did not(subjects that required Treatment require additional additionalantimicrobial Age group arm antibiotic therapy) therapy) ChildrenFoamOtic 96.30% (52/54) 3.70% (2/54) Ciprodex ® 95.74% (45/47) 4.26%(2/47) Adult FoamOtic 93.02% (40/43) 6.98% (3/43) Ciprodex ® 96.36%(53/55) 3.64% (2/55)

Time to end-of-pain: Kaplan-Meier survival curves based on the censoreddata of the pain dairies showed that the time to end of pain was similarbetween the two treatment groups (p value of log-rank test=0.8163,FIG. 1) The median time to end of pain was 3.97 days in the FoamOticgroup and 4.58 days in the Ciprodex treated group (Table 22 below).Comparable results were obtained when looking at the 75 and 25percentile. Therefore, FoamOtic containing only ciprofloxacin andapplied once daily stopped the pain in a similar way as ear dropsapplied twice daily that contain a steroid (dexamethasone) in additionto ciprofloxacin.

TABLE 22 Estimated time to end of pain in the groups of subjects treatedwith FoamOtic or Ciprodex ® Time to end of pain (days since treatmentstart) Quartile estimates FoamOtic (n = 97) Ciprodex ® (n = 102) 75 6.496.48 50 3.97 4.58 25 2.63 2.85

Thus, the present results demonstrate the clinical efficacy of the oticfoam compared to commercial ear drops. The results show that whenadministered once daily in the form of otic foam, a lower dose ofciprofloxacin in the absence of an anti-inflammatory steroid providesthe same relief as the combination of ciprofloxacin and dexamethasone inthe form of ear drops applied twice daily.

These results clearly indicate that the otic foam of the presentinvention presents an advantage over commercially ear drops by achievingthe desired therapeutic effect in treating acute otitis externa withapproximately half of the amount of the antibiotic agent and without theneed of the steroid present in the Ciprodex® pharmaceutical compositionapplied twice daily.

It will be appreciated by persons skilled in the art that the presentinvention is not limited by what has been particularly shown anddescribed herein above. Rather the scope of the invention is defined bythe claims that follow.

The invention claimed is:
 1. A foamable otic pharmaceutical compositioncomprising: (a) an oil-in-water emulsion comprising: (i) an antibioticagent in an amount effective for antibacterial action; (ii) an analgesicor anesthetic agent; (iii) water in an amount of at least 75% (w/w) ofthe total weight of the emulsion; (iv) mineral oil in an amount of nomore than 15% (w/w) of the total weight of the emulsion; (v) a syntheticsurfactant pharmaceutically acceptable for otic use; (vi) a foamingagent selected from a fatty alcohol and a fatty acid; (vii) whitepetrolatum in an amount that does not exceed 3% (w/w) of the totalweight of the emulsion; and (b) a compressed propellant gas; wherein theoil-in-water emulsion is devoid of organic polar co-solvents, theorganic polar co-solvents being polyols, wherein the oil-in-wateremulsion has an osmolarity of about 280 mOsm/L to about 320 mOsm/L, andwherein the composition, packaged in a container, is adapted to form afoam after dispensing from the container.
 2. The foamable oticpharmaceutical composition according to claim 1, wherein the antibioticagent is a quinolone antibiotic agent.
 3. The foamable oticpharmaceutical composition according to claim 2, wherein the quinoloneantibiotic agent is selected from the group consisting ciprofloxacin,ofloxacin, moxifloxacin, levofloxacin, marbofloxacin, enrofloxacin,finafloxacin, besifloxacin,7-[(3E)-3-(2-Amino-1-fluoroethylidene)-1-piperidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (JNJ-Q2),orbifloxacin, delafloxacin, pradofloxacin, and salts thereof.
 4. Thefoamable composition according to claim 3, wherein ciprofloxacin isciprofloxacin HCl.
 5. The foamable composition according to claim 1,wherein the analgesic or anesthetic agent is selected from the groupconsisting of benzocaine, tetracaine, procaine, and antipyrine.
 6. Thefoamable otic pharmaceutical composition according to claim 1, whereinthe synthetic surfactant is selected from the group consisting ofpolysorbates, tylaxopol, glyceryl stearate, PEG stearate,polyoxyethylene fatty acid esters, polyoxyethylene alkyl ethers, andcombinations thereof.
 7. The foamable otic pharmaceutical compositionaccording to claim 1, wherein the fatty alcohol is selected from thegroup consisting of cetyl alcohol, stearyl alcohol, and cytostearylalcohol.
 8. The foamable otic pharmaceutical composition according toclaim 1, wherein the polyol is selected from the group consisting ofglycerol, propylene glycol, hexylene glycol, diethylene glycol, andpropylene glycol n-alkanol.
 9. The foamable otic pharmaceuticalcomposition according to claim 1, further comprising at least oneexcipient selected from the group consisting of a tonicity agent, a pHmodifying agent, disodium edetate, an antibacterial agent, ananti-oxidant, a preservative, and a gelling agent.
 10. The foamable oticpharmaceutical composition according to claim 1, wherein the compressedpropellant gas is a mixture of hydrocarbons present in an amount rangingfrom about 1% to about 8% by weight of the composition.
 11. The foamableotic pharmaceutical composition according to claim 1, wherein theoil-in-water emulsion comprises: Ciprofloxacin hydrochloride; (ii) ananalgesic or anesthetic agent; (ii) water in an amount ranging from 75%to 88% (w/w); (iii) mineral oil in an amount of 7% to 10% (w/w); (iv)PEG-40 stearate and glyceryl stearate; (v) cetyl alcohol in an amount ofabout 0.25% to about 2% (w/w); and (vi) white petrolatum in an amount ofabout 0.1% to about 1% (w/w).
 12. The foamable otic pharmaceuticalcomposition according to claim 11, further comprising a tonicity agent,a pH modifying agent, disodium edetate, and a gelling agent.
 13. Thefoamable otic pharmaceutical composition according to claim 11, furthercomprising dextrose as a tonicity agent, acetic acid and sodium acetateas pH modifying agents, disodium edetate, and hydroxyethylcellulose andpolyvinylpyrollidone as gelling agents.
 14. The foamable oticpharmaceutical composition according to claim 13 comprisingciprofloxacin HCl and an analgesic or anesthetic agent as active agents,and further comprising the following excipients: Excipients % (w/w)Water To complete to 100 Mineral oil 7 PEG-40 stearate and glyceyl 6stearate Cetyl alcohol 1.5 White petrolatum 1 Dextrose 0.5 Acetic acid0.1 Sodium acetate 0.1 EDTA (disodium edetate) 0.1 Hydroxyethylcellulose 0.3 polyvinylpyrrolidone 1.2.


15. A method for treating an ear disorder comprising administering tothe ear of a subject in need of such treatment a therapeuticallyeffective amount of a foamable otic pharmaceutical composition accordingto claim
 1. 16. The method according to claim 15, wherein the eardisorder is selected from the group consisting of external eardisorders, middle ear disorders, and inner ear disorders.
 17. The methodaccording to claim 16, wherein the external ear disorder is otitisexterna.